Depot medroxyprogesterone acetate and breast cancer: a systematic review.

PURPOSE: Short-acting progestin-only injectables containing depot medroxyprogesterone acetate (DMPA) are a safe method of contraception. Although DMPA has been available for several decades, there is little data on its influence on the risk of breast cancer. Hence, the aim of this paper was to provide an overview of the existing studies and create clarity regarding a possible association with breast cancer. METHODS: Literature searches were executed in MEDLINE, Embase, the Cochrane Library, ClinicalTrials.gov and ICTRP. Search terms were related to DMPA and breast cancer. After elimination of duplicates, 3'850 studies were identified and assessed according to inclusion and exclusion criteria. Finally, ten studies were selected and included in this review. RESULTS: All the selected papers were case-control-studies, except for one pooled analysis and one study comparing observed and expected number of cancer cases. Most of the included studies found no overall elevated breast cancer incidence in DMPA users, only one study found a slightly increased risk and two studies concluded with a significant increase for the overall breast cancer risk. CONCLUSION: There is little evidence that DMPA may increase the overall risk for breast cancer. However, the incidence of breast cancer is possibly increased in current and more recent users, especially in women younger than 35 years. Long-term use did not result in any risk increase. Nevertheless, further studies will be necessary to confirm these findings and weigh up the individual risks and benefits of this contraceptive method.

Injectable contraceptive Depo-Provera induces erratic beating patterns in patient-specific induced pluripotent stem cell-derived cardiomyocytes with long QT syndrome type 2.

BACKGROUND: Long QT syndrome type 2 (LQT2) is caused by pathogenic variants in KCNH2. LQT2 may manifest as QT prolongation on an electrocardiogram and present with arrhythmic syncope/seizures and sudden cardiac arrest/death. Progestin-based oral contraceptives may increase the risk of LQT2-triggered cardiac events in women. We previously reported on a woman with LQT2 and recurrent cardiac events temporally related and attributed to the progestin-based contraceptive medroxyprogesterone acetate ("Depo-Provera" [Depo] MilliporeSigma, Catalog# 1378001, St. Louis, MO). OBJECTIVE: The purpose of this study was to evaluate the arrhythmic risk of Depo in a patient-specific induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) model of LQT2. METHODS: An iPSC-CM line was generated from a 40-year-old woman with p.G1006Afs∗49-KCNH2. A CRISPR/Cas9 gene-edited/variant-corrected isogenic control iPSC-CM line was generated. FluoVolt (Invitrogen, F10488, Waltham, MA) was used to measure the action potential duration after treatment with 10 µM Depo. Erratic beating patterns characterized as alternating spike amplitudes, alternans, or early afterdepolarization-like phenomena were assessed using multielectrode array (MEA) after 10 µM Depo, 1 µM isoproterenol (ISO), or combined Depo + ISO treatment. RESULTS: Depo treatment shortened the action potential duration at 90% repolarization of G1006Afs∗49 iPSC-CMs from 394 ± 10 to 303 ± 10 ms (P < .0001). Combined Depo + ISO treatment increased the percentage of electrodes displaying erratic beating in G1006Afs∗49 iPSC-CMs (baseline: 18% ± 5% vs Depo + ISO: 54% ± 5%; P < .0001) but not in isogenic control iPSC-CMs (baseline: 0% ± 0% vs Depo + ISO: 10% ± 3%; P = .9659). CONCLUSION: This cell study provides a potential mechanism for the patient's clinically documented Depo-associated episodes of recurrent ventricular fibrillation. This in vitro data should prompt a large-scale clinical assessment of Depo's potential proarrhythmic effect in women with LQT2.

A Rare Case of Splenic Artery Thrombosis Provoked By Medroxyprogesterone Acetate Requiring Splenectomy.

Splenic artery thrombosis is estimated to occur in only 0.016% of hospital admissions. Hormonal contraception is known to have hypercoagulable side effects, but splenic artery thrombosis (SAT) followed by functional autosplenectomy is a very rare side effect. We report a case of a 48-year-old female with persistent SAT provoked by depot medroxyprogesterone acetate (DMPA). She initially presented with severe left lower quadrant abdominal pain, and imaging revealed an extensive thrombus in the splenic artery. She was immediately started on intravenous heparin, and her symptoms improved after a few days, at which point she was discharged on oral apixaban. Three months after discharge, the patient presented with symptoms similar to the initial presentation. Further history revealed that she received an injectable DMPA shot prior to her initial admission. Other possible causes of SAT were ruled out. On imaging, her previous thrombus had increased in size and now filled the entire splenic artery. Therefore, the patient underwent robotic splenectomy with remarkable improvement in her symptoms. This case represents a rare clinical manifestation of a hypercoagulable state induced by DMPA. We review the existing literature to explain the epidemiology, presentation, diagnosis, and treatment of SAT, and incorporate our patient's presentation into the existing literature regarding the effect of contraception in inducing thrombotic events.

A Rare Case of Persistent ST-Elevation Myocardial Infarction Post-Tissue Plasminogen Activator With White Clot Extraction in a Middle-Aged Woman on Medroxyprogesterone Acetate.

ST-elevation myocardial infarction (STEMI) occurs when vulnerable intravascular plaques rupture and produce eventual occlusion of the coronary circulation. With the increased prevalence of coronary artery disease, STEMIs and NSTEMIs are very well-studied and have generally been known to be caused by red and white thrombi, respectively. STEMIs have been more commonly associated with red clots, while NSTEMIs tend to be caused by white clots. Recent studies have also shown that a third of STEMIs are due to white clot formation, resulting in transmural infarction, most commonly seen at the coronary artery bifurcation. However, no cases of white clot STEMIs post-recombinant tissue plasminogen activator (rTPA) administration have been described in the literature. The data regarding the utility of rTPA in lysing white clots is limited, questioning the overall efficacy of rTPA with white clot lysis. This case report presents a patient on depot contraceptive who had a persistent STEMI despite rTPA administration and was found to have formed a white clot, which was extracted on thrombectomy. As this unique presentation and its associated risk factors are explored in the future, we hope that this case report contributes to the body of knowledge in the detection and management of white clot MIs in the context of rTPA efficacy.

Depo Medroxyprogesterone (DMPA) Promotes Papillomavirus Infections but Does Not Accelerate Disease Progression in the Anogenital Tract of a Mouse Model.

Contraceptives such as Depo-medroxyprogesterone (DMPA) are used by an estimated 34 million women worldwide. DMPA has been associated with increased risk of several viral infections including Herpes simplex virus-2 (HSV-2) and Human immunodeficiency virus (HIV). In the current study, we used the mouse papillomavirus (MmuPV1) anogenital infection model to test two hypotheses: (1) contraceptives such as DMPA increase the susceptibility of the anogenital tract to viral infection and (2) long-term contraceptive administration induces more advanced disease at the anogenital tract. DMPA treatments of both athymic nude mice and heterozygous NU/J (Foxn1nu/+) but ovariectomized mice led to a significantly increased viral load at the anogenital tract, suggesting that endogenous sex hormones were involved in increased viral susceptibility by DMPA treatment. Consistent with previous reports, DMPA treatment suppressed host anti-viral activities at the lower genital tract. To test the impact of long-term contraceptive treatment on the MmuPV1-infected lower genital tract, we included two other treatments in addition to DMPA: 17ß-estradiol and a non-hormone based contraceptive Cilostazol (CLZ, Pletal). Viral infections were monitored monthly up to nine months post infection by qPCR. The infected vaginal and anal tissues were harvested and further examined by histological, virological, and immunological analyses. Surprisingly, we did not detect a significantly higher grade of histology in animals in the long-term DMPA and 17ß-estradiol treated groups when compared to the control groups in the athymic mice we tested. Therefore, although DMPA promotes initial papillomavirus infections in the lower genital tract, the chronic administration of DMPA does not promote cancer development in the infected tissues in our mouse model.

Ovulation suppression following subcutaneous administration of depot medroxyprogesterone acetate.

Objectives: To characterize the relationship between serum medroxyprogesterone acetate (MPA) concentrations and ovulation suppression, and to estimate the risk of ovulation for investigational subcutaneous regimens of Depo-Provera CI (Depo-Provera) and Depo-subQ Provera 104 (Depo-subQ). Study Design: We performed a secondary analysis of 2 studies that assessed the pharmacokinetics and pharmacodynamics of MPA when Depo-Provera is administered subcutaneously rather than by the labeled intramuscular route. Each woman received a single 45 mg to 300 mg subcutaneous injection of Depo-Provera, a single 104 mg subcutaneous injection of Depo-subQ, or 2 injections of Depo-subQ at 3-month intervals. We used an elevation of serum progesterone ≥4.7 ng/mL as a surrogate for ovulation and non-parametric statistical methods to assess pharmacokinetic and pharmacodynamic relationships. Results: This analysis included 101 women with body mass index (BMI) 18 to 34 kg/m2. Return of ovulation occurred at a median MPA concentration of 0.07 ng/mL (95% CI: 0.06-0.08) and the 90th percentile was 0.10 ng/mL (95% CI: 0.09-0.14). Neither age, race, nor BMI significantly influenced this relationship. The estimated probabilities of ovulation within 4 months of a 104 mg subcutaneous injection and within 7 months of a 150 mg subcutaneous injection (6 plus a 1-month grace) were each below 2.2%. Conclusions: The typical MPA concentration associated with loss of ovulation suppression is substantially less than the commonly cited threshold of 0.2 ng/mL. Based on our results, MPA levels would rarely be low enough to permit ovulation if the Depo-subQ reinjection interval were extended to four months or if 150 mg Depo-Provera were injected subcutaneously every 6 months. Implications: Extending the three-month Depo-subQ reinjection interval by one month would result in a 25% reduction in yearly MPA exposure, with little risk of pregnancy. Off-label subcutaneous administration of 150 mg Depo-Provera every 6 months would be a highly effective repurposing of an excellent product, with a similar reduction in cumulative exposure.

"I know my body and I just can't get pregnant that easily" - Women's use and non-use of the injection to manage fertility.

Approximately one-third of contraceptive users in Malawi use the Depo-Provera injection, a method that must be re-injected every three-months to prevent pregnancy and may reduce fecundity for a time after discontinuation. Little is known about how women use the injection to achieve their desired family size. In 2018, we conducted 20 in-depth interviews with women who were part of a cohort study in rural Malawi. Interviews focused on contraceptive decision-making. Data were indexed (summarized) and coded using narrative, process, and thematic codes. Women described the importance of knowing about their "natural" fertility by having children prior to ever using contraception because women considered contraception to have a potential negative effect on fertility. Women then applied what they learned about their fertility (i.e., how easy/difficult it was to become pregnant) to manage their fertility over their reproductive life-course. As part of fertility management, women frequently described using the injection less frequently than clinically recommended, using signs from their body (e.g., menstruation) to determine when to reinject. Managing fertility through subclinical injection use was viewed as a way to optimize women's' chances of preventing unintended pregnancy while maintaining their ability to become pregnant when they wanted to. Women wanted to play an active role in managing their fertility and were not passive consumers of contraception. It is therefore critical that family planning programs provide contraceptive counseling to women that engages their desire to manage their fertility, acknowledges their concerns about fertility, and helps them choose a method that best fits their needs.

In the name of science: Ethical violations in the ECHO randomised trial.

It was in the 1990s, that the possibility of increased transmission of HIV with the use of injectable contraceptive Depo-Provera®, was first flagged in medical literature. This has posed a challenge for its use in countries, particularly in the African region, where the prevalence and transmission rate of HIV is high. In 2015, a randomised 'clinical' trial, the Evidence for Contraceptive Options and HIV Outcomes (ECHO) was launched in four African countries to resolve the question whether the increased risk was causal. Contrary to expectations, the ECHO trial successfully recruited and randomised the specified number of girls/women participants. This paper argues that this was made possible by exercising undue influence, by using incentives, coercive language, and by concealing the real nature of the clinical trial during recruitment. The ECHO trial is unique in subjecting a group of healthy girls/women knowingly to a contraceptive drug with an intention not of finding out whether it is efficacious as a contraceptive, but to find out how risky or life-threatening its use could be. Thus, the ECHO trial has violated one of the central tenets of the Helsinki Declaration by privileging pursuit of knowledge over the interests of the girl/women trial participants from Africa.

Suppression of ovulation and pharmacokinetics following subcutaneous administration of various doses of Depo-Provera®: a randomized trial.

OBJECTIVES: To identify the lowest dose of Depo-Provera that, when administered off-label subcutaneously, suppressed ovulation and had a pharmacokinetic profile consistent with a 4-month contraceptive effect. STUDY DESIGN: We conducted a randomized, multicenter, parallel-group study to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of medroxyprogesterone acetate (MPA) after subcutaneous injection of three different doses of Depo-Provera. We randomized sixty women between 18 and 40 years of age at low risk of pregnancy with confirmed ovulation and body mass index of 18 to 35 kg/m2 to receive a single injection of 45, 75 or 105 mg of Depo-Provera, or a single injection of Depo-subQ provera 104 as a reference drug (15 women per group) and followed them for 7.5 months. We evaluated suppression of ovulation as the primary outcome, and MPA concentrations, pharmacokinetic parameters, safety, and local tolerability as secondary outcomes. RESULTS: Five women ovulated within four months of treatment initiation (three in the 45 mg group and two in the 75 mg group). MPA levels associated with ovulation were in general low, largely ≤ 0.2 ng/mL (the presumed contraceptive threshold). No women in either the 105 mg group or the Depo-subQ provera 104 group ovulated within four months. The PK parameters including Cmax, C119, and AUC0-119 for these 2 groups were similar but not equivalent. CONCLUSION: A dose of 105 mg of Depo-Provera injected subcutaneously was the lowest tested dose that consistently suppressed ovulation and maintained serum MPA levels consistent with contraceptive effect for at least 4 months. The PK and PD results for the 105 mg dose were similar to Depo-subQ provera 104 over this period.

Effect of Postpartum Depo Medroxyprogesterone Acetate on Lactation in Mothers of Very Low-Birth-Weight Infants.

Objective: This study examined the effect of postpartum administration of depo medroxyprogesterone acetate (DMPA) on milk production, time to onset of secretory activation, lactation duration, and infant consumption of mother's own milk (MOM) in mothers of preterm very low-birth-weight (VLBW) infants. Materials and Methods: We conducted a secondary analysis of data from mothers who delivered infants weighing ≤1,500 g and at ≤32 weeks' gestation. The volume of milk produced was measured on days 1-7, 14, and 21 by weighing all expressed milk on an electronic scale. Time to secretory activation was determined through self-report of a feeling of breast fullness. Information on lactation duration and the percent of feeds consisting of MOM consumed by infants was obtained from the medical records. Results: Mothers who received postpartum DMPA were more likely to be African American (72.4% versus 31.4%; p = 0.0006), unemployed (65.5% versus 44.5%; p = 0.027), and Medicaid eligible (89.7% versus 67.2%; p = 0.019). There were no differences in daily milk production between mothers who received DMPA before hospital discharge (n = 29) compared with those who did not (n = 141). When mothers who reached secretory activation before receiving DMPA were removed from analysis, receiving DMPA was associated with a later onset of secretory activation (103.7 versus 88.6 hours; p = 0.028). There were no statistically significant differences between the study groups in lactation duration or infant MOM consumption. Conclusions: DMPA, when administered postpartum to mothers of preterm VLBW infants, delayed secretory activation, but had no detrimental effect on milk production or lactation duration. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT01892085.

The potential for intramuscular depot medroxyprogesterone acetate as a self-bridging emergency contraceptive.

OBJECTIVE: To examine the rate of ovulatory disruption when intramuscular depot medroxyprogesterone acetate (DMPA) is administered across graded stages of dominant follicle development. STUDY DESIGN: We assigned enrolled participants to one of three preassigned dominant follicle size groups: 12-14 mm, 15-17 mm and ≥ 18 mm. We followed dominant follicles via serial transvaginal ultrasound (TVUS) until the follicles reached their assigned size, at which time we administered DMPA. For 5 consecutive days thereafter, we followed the follicles via TVUS to observe follicle rupture and obtained serum luteinizing hormone (LH), estradiol, and progesterone concentrations. In the following 2 weeks, we collected serum progesterone concentrations twice weekly to detect possible ovulatory delay or dysfunction. We also collected serum medroxyprogesterone acetate (MPA) concentrations at 1 and 24 h after DMPA administration to examine against ovulatory outcomes. RESULTS: Twenty-six of 29 enrolled women completed the study. DMPA suppressed ovulation in 17/26 (65%) and caused ovulatory dysfunction in 1/26 (4%) participants. Larger follicles were more likely to rupture despite DMPA (12-14 mm: 0/10 (0%); 15-17 mm: 3/10 (30%); ≥ 18 mm: 6/6 (100%); p < .01). Pre-DMPA LH concentrations ranged from 13.8 to 93.7 IU/L (mean 49.0 IU/L) in cases of follicle rupture. We observed no cases of follicle rupture when DMPA was administered through cycle day 12. All 24-h MPA concentrations exceeded those needed for ovulation suppression. CONCLUSION: DMPA suppressed and additionally disrupted ovulation in 65% and 4% of observed cycles, respectively. DMPA may provide effective emergency contraception as well as ongoing contraception if administered prior to an expected ovulation and specifically before the LH surge. IMPLICATIONS: DMPA may be an alternative form of emergency contraception that can also self-bridge to ongoing contraception. As ovulation was not observed among any follicles when DMPA was given through cycle day 12, women who initiate DMPA up through cycle day 12 may not require backup contraception.

Reasons for hormonal contraceptive use in a cohort of African-American women living in the Detroit area.

OBJECTIVES: To characterize reasons for hormonal contraceptive (HC) use in 1,455 African-American women, aged 23-35 years. STUDY DESIGN: The community-based cohort members were recruited from the Detroit, Michigan area in 2010-2012. HC history was collected via telephone interview. RESULTS: Seven percent reported HC use exclusively for non-contraceptive purposes, and 49% reported non-contraceptive reasons in addition to contraception. Non-contraceptive reasons were reported for all HC types, but were most common for combined oral contraceptives. Primary reasons were for irregular cycles, heavy bleeding, and pain. CONCLUSIONS: In this large cohort of Black women, HC use to treat menstrual problems was common. IMPLICATIONS: HCs were commonly used for both pregnancy prevention and management of menstrual symptoms, but some women used HCs exclusively for menstrual symptom relief. The importance for women of non-contraceptive reasons for HC use may not be adequately recognized, and published data on Black women's reasons for HC use remain limited.

Precipitous Delivery Masquerading as Biliary Colic in the Setting of Depo-Provera® Failure.

Precipitous delivery in the emergency department is a high-acuity, low-occurrence event that requires rapid recognition and interdepartment cooperation to prevent fetal and maternal morbidity and mortality. Prompt recognition of the peripartum state can be delayed by reported usage of long-acting contraception and concurrent distracting complaints. In this case report, a young female presented to the emergency department with epigastric abdominal pain in the setting of recent workup for biliary colic and multiple doses of long-acting, depot contraceptive agents. Early utilization of bedside ultrasound confirmed a full-term, intrauterine pregnancy as well as an impacted gallbladder stone, followed by a precipitous footling breech presentation that required an emergent cesarean section.

Is the Injectable Contraceptive Depo-Medroxyprogesterone Acetate (DMPA-IM) Associated with an Increased Risk for HIV Acquisition? The Jury Is Still Out.

Intramuscular depo-medroxyprogesterone acetate (DMPA-IM) is the most widely used hormonal contraceptive in sub-Saharan Africa. Previous meta-analyses of observational studies found a significant 40%-50% increased risk associated with DMPA-IM use, relative to no contraception or infrequent condom use. This raised substantial concerns, although these studies had important limitations. Consequently, the open-label randomized Evidence for Contraceptive Options and HIV Outcomes trial was conducted, designed primarily to detect a 50% or greater difference in HIV risk between DMPA-IM, the levonorgestrel (LNG) implant, and the copper-intrauterine device. The ECHO study, published in July 2019, concluded that there is no substantial difference in HIV risk among the methods evaluated, and that all three methods are safe and highly effective. In response, the WHO relaxed the Medical Eligibility Criteria for DMPA-IM use among women at high HIV risk in August 2019. However, two of the three comparisons in the ECHO trial could rule out neither a 50% increase nor no change in HIV risk for one contraceptive compared with another. The study had limitations and the results contained considerable uncertainty. They also did not inform on associated HIV risk for any one of the individual methods due to the absence of a control group such as no contraception or only infrequent condom use. The HIV risks associated with LNG implant and copper-IUD relative to no contraception or infrequent condom use are unknown and these cannot be seen as controls, nor did the authors claim them to be. The results will be discussed in the context of their limitations, what they add to the body of work to date on contraception and HIV acquisition, and the implications of the findings and reports thereof for future research and contraceptive choice.

Changes in body weight and blood pressure among women using Depo-Provera injection in Northwest Ethiopia.

OBJECTIVES: Depo-Provera is an injectable contraceptive method containing medroxyprogesterone acetate. It has some adverse effects like changes in menstrual pattern, loss in bone mineral density and risk of weight gain. Therefore, this study is aimed at to investigate the effects of Depo-Provera on body weight and blood pressure among Ethiopian women. Institution based cross-sectional study design was conducted from January 2017 to April 2017. Data were analyzed using SPSS version 21 software. Paired t test, independent t-test and ANOVA were used to evaluate the presence of mean difference and relationship between changes in variables and duration of use of Depo-Provera. P-value ≤ 0.05 were considered as statistically significant. RESULTS: The mean weight and body mass index (BMI) of Depo-Provera users were increased significantly (p = 0.02 for mean body weight and p = 0.019, for body mass index). There was no significant difference in mean arterial blood pressure (MAP) of Depo-Provera users compared to controls or their respective pretreatment value (p-value = 0.85 for Depo-Provera users and 0.67 for non-users). The finding of this study revealed that there is an increased weight gain and BMI among Depo-Provera users compared to non-users, which really requires attention of health professionals and other stake holders.

Why Didn't You Text Me? Poststudy Trends From the DepoText Trial.

OBJECTIVE: To evaluate the longitudinal impact of a 9-month text message intervention on participant adherence beyond the intervention to highly effective contraceptive methods among urban adolescent and young adult women enrolled in the DepoText randomized control trial (RCT). STUDY DESIGN: Retrospective longitudinal cohort study of long-term follow-up data from the DepoText RCT. Sixty-seven female participants (aged 13-21 years) using depot medroxyprogesterone acetate (DMPA) were recruited from an urban academic adolescent practice in Baltimore, Maryland. The principal outcome measured was a comparison of contraceptive method choice between the control and intervention groups during the 20 months postintervention. RESULTS: Intervention participants were 3.65 times more likely to continue using DMPA or a more efficacious method at the 20-month postintervention evaluation (odds ratio 3.65, 95% CI 1.26-10.08; P = .015). CONCLUSION: Participation in the DepoText trial was associated with continued use of DMPA or a more effective contraceptive method almost 20 months after the intervention exposure ended.

Review on the Biological Mechanisms Associated with Depo-Provera and HIV-1 Risk Acquisition in Women.

Women constitute more than 50% out of millions of individuals infected with HIV-1, the major causative agent of acquired immune deficiency syndrome. About 40% of HIV-1 infections have been reported to initiate in the female reproductive tract. However, the mechanisms through which these infections are spread are poorly understood; hence, there is now a major concern in women who use long acting injectable hormonal contraceptives, particularly Depo-Provera and an increase of HIV-1 risk acquisition. Based on literature, Depo-Provera has an affinity for both the glucocorticoid receptor and the progesterone receptor in the female reproductive tract. Therefore, investigating HIV-1 pathogenesis in the female reproductive tract via the glucocorticoid receptor and the progesterone receptor mechanisms in response to the effect of Depo-Provera is of great importance.